Melanocortin Receptor Ligands: New Horizons for Skin Biology and Clinical Dermatology

Department of Dermatology and Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, University of Münster, Germany.
Journal of Investigative Dermatology (Impact Factor: 7.22). 08/2006; 126(9):1966-1975. DOI: 10.1038/sj.jid.5700421


The melanocortin (MC) system is probably the best characterized neuropeptide network of the skin. Most cutaneous cell types express MC receptors (MC-Rs) and synthesize MCs, such as -melanocyte-stimulating hormone (-MSH), that act in autocrine and paracrine fashion. In human skin cells, activation of adenylate cyclase by MCs occurs at 10-6–10-9 M doses of the ligand, but effects are induced in some cell types at subnanomolar concentrations. In addition to the pigmentary action of MCs on epidermal melanocytes, the hair follicle is a source and target for MCs. MCs regulate lipogenesis in sebocytes expressing both MC-1R and MC-5R. In adipocytes, lipid metabolism is modulated by agouti signalling protein, a natural MC-1R/MC-4R antagonist. The anti-inflammatory activity of -MSH includes immunomodulatory effects on several resident skin cells and antifibrogenic effects mediated via MC-1R expressed by dermal fibroblasts. In human mast cells, -MSH appears to be proinflammatory due to histamine release. -MSH exhibits cytoprotective activity against UVB-induced apoptosis and DNA damage, a finding that helps explain the increased risk of cutaneous melanoma in individuals with loss of function MC-1R mutations. These findings should improve our understanding of skin physiology and pathophysiology and may offer novel strategies with MCs as future therapeutics for skin diseases.Abbreviations: AGRP, agouti-related peptide; AP, agouti protein; ASP, Agouti signalling protein; GRK, G protein-coupled receptor kinase; LPS, lipopolysaccharide; MC, melanocortin; Mc-r, (murine) melanocortin receptor; MC-R, (human) melanocortin receptor; MSH, melanocyte-stimulating hormone; POMC, proopiomelanocortin; RHC, red hair and fair skin; TGF-, transforming growth factor-; TM, transmembrane; TNF-, tumor necrosis factor-

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    • "MC1R is not only expressed on melanocytes but also on non-melanocytic cutaneous cells as well as on cells regulating immune responses and inflammation, e.g. gut mucosa, dendritic cells, macrophages, mast cells and neutrophils (for review [29]). Furthermore, MC1R is also expressed on chondrocytes [30] suggesting a role in bone formation. "
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    ABSTRACT: Background An increasing number of studies report that Cthrc1 is expressed in various cancer cells. The present study sought to identify which cells in tumors and remodeling tissues express Cthrc1 and investigate the range of circulating human Cthrc1 levels in health and disease. Methodology/Principle Findings Highly specific monoclonal antibodies were generated to detect Cthrc1 by ELISA in plasma and in tissues by immunohistochemistry. In human colon, gastric, breast, endometrial, pancreatic, kidney, lung and skin cancer, Cthrc1 was expressed by activated stromal cells and not the cancer cells themselves. Similarly, conditions evoking tissue remodeling, such as wound repair or angiotensin II-mediated hypertension, induced Cthrc1 expression in interstitial and adventitial fibroblasts and perivascular stromal cells. Levels of Cthrc1 in plasma from healthy subjects were near the lower detection limit except for individuals with red hair, who had up to several hundred fold higher levels. Elevated Cthrc1 was also found in patients with diabetes, inflammatory conditions, and infections, but not solid tumors. Transgenic mouse studies suggested that Cthrc1 expression by stromal cells does not contribute to circulating levels. In human pituitaries, Cthrc1 was expressed in the anterior and intermediate lobes with unencapsulated Cthrc1 accumulations typically surrounded by chromophobe cells. Conclusions We identify Cthrc1 as a marker for activated stromal cells. Cthrc1 is a pituitary hormone with significantly elevated levels in subjects carrying variant alleles of the melanocortin-1 receptor as wells as in patients with inflammatory conditions.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Specifically, binding of α-MSH (one of the derivatives of POMC) to MC1R stimulates cAMP in the melanocyte that, in turn, leads to activation of downstream transcription factors. Of note, variants of MCR1 are important in the determination of skin types, hair color, response to tanning and propensity to develop melanoma.31,135 One HRE site was found to be located at the -248 position and two HREs were found to be located at the +209 and +383 positions of POMC gene. "
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    ABSTRACT: Hypoxia-inducible factor-1α (HIF-1α) is a highly oxygen sensitive bHLH protein that is part of the heterodimeric HIF-1 transcription factor. Under hypoxic stress, HIF-1 activity is induced to control expression of multiple downstream target genes, including vascular endothelial growth factor (VEGF). The normal epidermis exists in a constant mild hypoxic microenvironment and constitutively expresses HIF-1α and HIF-2α. Expression of HIF-1α and/or HIF-2α has been suggested to correlate with the increased malignant potential of melanocytes, therefore, failures of melanoma therapies may be partially linked to high HIF activity. Notably, melanomas that have the V600E BRAF mutation exhibit increased HIF-1α expression. We have utilized a bioinformatics approach to identify putative hypoxia response elements (HREs) in a set of genes known to participate in the process of melanogenesis (includingTRPM1, SLC45A2, HRAS, C-KIT, PMEL and CRH). While some of the mechanistic links between these genes and the HIF pathway have been previously explored, others await further investigation. Although agents targeting HIF activity have been proposed as novel treatment modalities for melanoma, there are currently no clinical trials in progress to test their efficacy in melanoma.
    Full-text · Article · Apr 2013 · Dermato-Endocrinology
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    • "The role of melanocortin 1 receptor and its ligand, α-MSH, in cutaneous wound repair remains to be determined despite evidence implicating α-MSH in the regulation of both inflammation and fibroproliferation (Bohm et al. 2006; Brzoska et al. 2008), known responses to cutaneous injury. In this study, we report the localization of MC1R and α-MSH to inflammatory cells and epidermal keratinocytes in murine cutaneous wounds and to epidermal keratinocytes and dermal fibroblasts in human acute burns and hypertrophic scars. "
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    ABSTRACT: Growing evidence indicates that the melanocortin 1 receptor (MC1R) and its ligand α-melanocyte-stimulating hormone (α-MSH) have other functions in the skin in addition to pigment production. Activation of the MC1R/α-MSH signaling pathway has been implicated in the regulation of both inflammation and extracellular matrix homeostasis. However, little is known about the role of MC1R/α-MSH signaling in the regulation of inflammatory and fibroproliferative responses to cutaneous injury. Although MC1R and α-MSH localization has been described in uninjured skin, their spatial and temporal expression during cutaneous wound repair has not been investigated. In this study, the authors report the localization of MC1R and α-MSH in murine cutaneous wounds, human acute burns, and hypertrophic scars. During murine wound repair, MC1R and α-MSH were detected in inflammatory cells and suprabasal keratinocytes at the leading edge of the migrating epithelial tongue. MC1R and α-MSH protein levels were upregulated in human burn wounds and hypertrophic scars compared to uninjured human skin, where receptor and ligand were absent. In burn wounds and hypertrophic scars, MC1R and α-MSH localized to epidermal keratinocytes and dermal fibroblasts. This spatiotemporal localization of MC1R and α-MSH in cutaneous wounds warrants future investigation into the role of MC1R/α-MSH signaling in the inflammatory and fibroproliferative responses to cutaneous injury. This article contains online supplemental material at Please visit this article online to view these materials.
    Full-text · Article · Mar 2011 · Journal of Histochemistry and Cytochemistry
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